Benzazonine derivatives



United States Patent U.S. Cl. 260293 9 Claims ABSTRACT OF THE DISCLOSURE The compounds are of the class of 1,2,3,5,6,7-hexahydro-benzazonines, useful for their pharmacological properties as anti-inflammatory agents.

This application is a continuation-in-part of my copending application, Ser. No. 636,250, filed May 5, 1967.

The subject benzazonines may be structurally represented by the following formulae:

/ HO R2 NIE[ 1 wherein R is a member selected from the group consisting of hydrogen and phenyl; and

B (II) wherein R is a member selected from the group consisting of benzyl and B-phenethyl and R and R are members selected from the group consisting of lower alkylcarbonyloxy; and

R1Q2 NRz (III) wherein R is a member selected from the group consisting of hydroxyl and lower alkylcarbonylamido, R is phenyl when R is hydroxyl and R is hydrogen when R is lower alkylcarbonylamido; R and R taken together is a member selected from the group consisting of oxo and oximino; R is a member selected from the group consisting of benzyl and B-phenethyl; and the nontoxic acid addition salts and the therapeutically active lower alkyl quaternary ammonium derivatives of compounds represented by Formula III.

The therapeutically active non-toxic acid addition salts of the basic nitrogen-containing compounds are prepared by treatment with an appropriate acid such as an inorganic acid, e.g., hydrochloric, hydrobromic, hydriodic, sulfuric, nitric or phosphoric; an organic acid such as acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, maleic, malic, fumaric, tartaric, citric, 'benzoic, mandelic, cinnamic, methane sulfonic, benzene sulfonic, salicylic, 2-phenoxybenzoic. Conversely, the salt form may be converted in the usual manner into the free base.

The novel basic nitrogen-containing compounds may be converted into the corresponding quaternary ammonium compounds by reaction of the tertiary bases with alkylating agents, i.e., alkyl or aralkyl halides or esters formed by reacting alkanols with an oxygen-containing acid such as methyl iodine, ethyl bromide, propyl chlo- 3,493,578 Patented Feb. 3, 1970 ride; lower alkenyl halides-allyl bromide; dilower alkylsufates-dimethylsulfate, diethylsulfate; lower alkylarylsulfonatesmethyl p-toluenesulfonate or aralkyl halidesbenzyl chloride. The quaternizing reaction may be performed in the presence or absence of a solvent, at room temperature or under cooling, at atmospheric pressure or in a closed vessel under pressure. Suitable solvents for this purpose are ethers such as diethylether or tetrahydrofuran, hydrocarbons such as benzene and heptane, ketones such as acetone and butanone, lower alkanols such as ethanol, propanol or butanol; or organic acid amides such as formamide or dimethylformamide. When lower alkyl halogenides are used as quaternizing agents, diethyl ether and benzene are the preferred solvents.

Certain of the novel compounds of this invention have been found to possess pharmacological activity as antiinfiammatory agents. The test used is known as the kaolininduced paw edema test. This test measures the ability of a compound, when administered in a single oral dose, to inhibit the swelling of the rat paw injected with a standard amount (0.1 ml.) of 10% kaolin suspension in saline. For comparative purposes, the activity of the compound to be tested is measured against that Produced by the known anti-inflammatory agent, phenylbutazone. In this assay, the test compound (0.4% suspension or 0.4% solution, depending on the compound) and phenylbutazone (0.4% solution) are administered in saline. Male Holtzman rats are used in the assay. The results are recorded in terms of percent inhibition produced by the compound and by phenylbutazone. The percent inhibition is calculated from the increase in circumference as the edema develops in the paw. The paw is measured immediately after injection with the kaolin suspension. The animal is then returned to the cage, allowing the edema to develop. After six hours, the circumference of the paw is again measured. In the kaolin rat paw edema test at doses of mg./ kilo orally the compound of Formula I where R is phenyl caused a 33% inhibition. The com pound of Formula III wherein R is hydroxyl, R is phenyl and R is benzyl caused a 26% inhibition. The compound of Formula III wherein R is propionylamide, R is hydrogen and R is phenethyl caused a 34% inhibition. The compounds of Formula II wherein R and R are lower alkyl carbonyloxy and R is benzyl or phenethyl are intermediates to the aforesaid active compounds. The compounds of Formula III where R and R taken together are oxo or oximino and R is phenethyl, and the compound where R and R taken together are 0x0 and R is benzyl are also intermediates to the aforesaid active compounds.

In preparing the compounds of this invention, dimethyl acetone-1,3-dicarboxylate and o-phthalaldehyde are reacted in a solvent such as benzene in the presence of pi-peridine and glacial acetic acid, with removal of water, for example, by azeotropic distillation to form dimethyl 7 oxo 7H-benzocycloheptene-6,8-dicarboxylate. This compound is reduced, for example by hydrogenation in the presence of platinum oxide catalyst to form 7-oxo- S,6,8,9 tetrahydro 7H benzocycloheptene-6,S-dicarboxylate. Reaction of this compound with fi-phenethyL amine in the presence of formaldehyde yields dimethyl l,2,3,5,6,7 hexahydro-l2-oxo-4-phenethyl-2,6-methano- 4H-4-benzazonine-2,6-dicarboxylate. Using benzylamine in place of p-phenethylamine, the corresponding 4-benzyl derivative is obtained. Hydrolysis and decarboxylation of the 2,6-dicarboxylic esters with phosphoric acid produces the corresponding 4-substituted-l,2,3,5,6,7-hexahydro- 2,6-methano-4H-4-benzazonin-12-ones. The 4-substituted- I,2,3,5,6,7 hexahydro 12-hydroxyimino-2,6-methano- 4H-4-benzazonines may be prepared by reacting the l,2,3,5,6,7 hexahydro 4 substituted-2,6-methano-4H- 4-benzazonin-12-one compounds with hydroxylamine hydrochloride in the presence of anhydrous sodium acetate in a suitable solvent such as ethanol. When the 1,2,3,5,6,7 hexahydro 4-substituted-2,6-methano4H-4- benzazonin-12-ones are reacted with organolithium reagents such as methyl lithium or phenyl lithium in inert solvents such as ether or benzene, the corresponding 12- substituted-lZ-alcohols are produced. The 1,2,3,5,6,7- hexahydro 4-substituted-2,6-methano-4H-4-benzazoninl2-ones may be reduced catalytically, for example with platinum in acetic acid, to give 1,2,3,5,6,7-hexahydro-4- substituted-2,6-methano-4H-4benzazonin-12-ols. The 12- lower alkyl carbonylamido compounds may be prepared by reducing the 1,2,3,5,6,7-hexahydro-12-hydroxyimino- 4-substituted-2,6-methano-4H-4-benzazonine compounds, for example, with lithium aluminum hydride in a suitable solvent such as tetrahydrofuran, and reacting the resulting product with a lower aliphatic anhydride.

The following examples are intended to illustrate, but not to limit, the scope of the present invention.

EMMPLE I The procedure described by Tarbell and Wargotz, J. Amer. Chem. Soc., 76, 5761 (1954) for the diethyl ester is followed. A solution of 34.7 grams (0.194 mole) of dimethyl acetone-1,3-dicarboxylate, 26.0 grams (0.194 mole) of o-phthalaldehyde, 2 ml .of piperidine and 8 ml. of glacial acetic acid in 200 ml. of benzene is heated under reflux with azeotropic removal of water until no more water comes off. The mixture is cooled and the precipitated solid is collected by filtration. The filtrate is concentrated in vacuo and the residue is triturated with methanol. Purification is effected by recrystallization from methanol. The product obtained is dimethyl 7-oxo-7H-benzocycloheptene-6,8-dicarboxylate, M.P. 186l88 C.

EXAMPLE II A suspension of 13.6 grams (0.05 mole) of dimethyl 7-oxo-7H-benzocycloheptene-6,S-dicarboxylate and 0.68 gram of platinum oxide in 100 ml. of glacial acetic acid is hydrogenated on a Parr shaker at 50 psi Heat is evolved during hydrogenation. The catalyst is removed by filtration, and the solvent is evaporated in vacuo. The residue is dissolved in hot hexane and is allowed to crystallize. The product obtained is dimethyl 7-oxo- 5,6,8,9 tetrahydro 7H benzocycloheptene-6,8-dicarboxylate, M.P. 84-88 C.

EXAMPLE III A solution of 7.3 grams (0.0264 mole) of crude dimethyl 7 oxo-5,6,8,9-tetrahydro-7H-benzocycloheptene- 6,8-dicarboxylate, 3.96 ml. (0.053 mole) of formalin and 2.9 ml. (0.0264 mole) of benzylamine in 20 ml. of methanol is heated under reflux for 1 hour. A solid separates on cooling and seeding. The mixture is stirred at room temperature for 18 hours. The solid is collected by filtration and recrystallized from methanol. The product obtained is dimethyl 4-benzyl-1,2,3,5,6,7-hexahydro 12-oxo-2,6-methano-4H-4-benzazonine-2,6-dicarboxylate, M.P. 142-143 C.

EXAMPLE IV A 2.7 gram (0.01 mole) sample of dimethyl 6,7,8,9- tetrahydro 7 oxo H-benzocycloheptene-6,8-dicarboxylate, 1.49 cc. (0.02 mole) of 40 percent aqueous formaldehyde solution and 1.21 grams (0.01 mole) of ,B-phenethylamine in 20 cc. methanol is refluxed 1 hour and is then allowed to stand at room temperature for 20 hours. The reaction mixture is evaporated to an oil which is dissolved in ether and treated with ethereal hydrogen chloride yielding a solid. After several recrystallizations from anhydrous ethanol, the product obtained is dimethyl 1,2,3,5,6,7 hexahydro-12-oxo-4phenethyl-2,6-methano- 4H-4-benzazonine-2,6-dicarboxylate hydrochloride, M.P.

4 EXAMPLE v A solution of 14.0 grams (0.0344 mole) of dimethyl 4 benzyl 1,2,3,5,6,7 hexahydro-l2-oxo-2,6-methano- 4H-4-benzazonine-2,6-dicarboxylate in 500 ml. of 60 percent phosphoric acid is heated under reflux with stirring for 18 hours. The reaction mixture is cooled, diluted with water and filtered. The filtrate is added with cooling and stirring to a solution containing one kilogram of potassium hydroxide. The resulting mixture is extracted 3 times with ether. The ether solution is washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crystalline material is recrystallized from methylcyclohexane. After recrystallization from 2 propanol followed by recrystallization from ether, the product obtained is 4 benzyl 1,2,3,5,6,7 hexahydro-2,6-methano-4H-4- benzazonin-lZ-one, M.P. 128130 C.

EXAMPLE VI A 5 gram (0.019 mole) sample of dimethyl 1,2,3,5,6,7- hexahydro 12 oxo-4-phenethyl-Z,6-methano-4H-4- benzazonine-Z,6-dicarboxylate hydrochloride is dissolved in 50 cc. of percent phosphoric acid, diluted with 50 cc. Water and then refluxed for 18 hours. The reaction mixture is cooled and treated with ice water yielding a suspension which is extracted with ether. The aqueous solution is made definitely basic with potassium hydroxide solution and the resulting suspension is extracted with ether. The ethereal solution is dried with magnesium sulfate and evaporated. The oil recovered is chromotographed on an alumina column using 1:1 benzene-petroleum ether to give a colorless eluate which upon evaporation yields an off-white solid. The solid is recrystallized from methylcyclohexane. The product obtained is 4- phenethyl 1,2,3,5,6,7-hexahydro-2,6-methano-4H-4-benzazonin-l2-one, M.P. 99l00 C.

EXAMPLE VII A mixture of 5 grams (0.0164 mole) 1,2,3,5,6,7-hexahydro 4-tphenethyl-2,6-methano-4H-4-benzazonin-12-one, 1.17 grams (0.0169 mole) hydroxylamine hydrochloride and 4.1 grams (0.05 mole) anhydrous sodium acetate is refluxed for 3 hours in cc. of 95 percent ethanol. Upon cooling, the reaction mixture is filtered to remove excess sodium acetate. The resulting filtrate is recrystallized from 95 percent ethanol. The product obtained is 1,2,3,5,6,7 hexahydro-12-hydroxyimino-4-phenethyl-2, 6-methano-4H-4-benzazonine, M.P. -151" C.

EXAMPLE VIII A 15.0 gram (0.0515 mole) sample of 1,2,3,5,6,7- hexahydro 4-benzyl-2,6-methano-4H-4-benzazonin-12- one in 13.4 grams (0.072 mole) of methyl p-toluenesulfonate is heated at 80 C. for 18 hours. The mixture is cooled and ground thoroughly with ether. The product obtained is 4-benzyl-1,2,3,5,6,7-hexanhydro-4-methyl-12- oxo-2,6-methano-4H-4-benzazoninium p-toluenesulfonate.

EXAMPLE IX A solution of methyl lithium [prepared by treating 0.68 gram (0.0984 mole) of freshly cut lithium wire in 20 cc. ether with 6.95 grams (0.0492 mole) of methyl iodide in 50 cc. ether] is treated with 5 grams (0.0164 mole) of 1,2,3,5,6,7 hexahydro 4 l phcnethyl 2,6 methano- 4H 4 benzazonin 12 one in 80 cc. ether and allowed to stir 18 hours at room temperature. The reaction mixture is filtered to remove excess lithium pieces which are promptly destroyed. The resulting filtrate is cooled and cautiously extracted several times with 3 N hydrochloric acid. The extracts are combined and made definitely basic with 25 percent sodium hydroxide yielding a suspension which is extracted with ether. The etheral solution is dried with magnesium sulfate and evaporated to an oil. The oily amine is converted to the hydrochloride salt which is recrystallized from ethanol-ether. The product obtained is 1,2,3,5,6,7 hexahydro 12 methyl 4 phenethyl 2,6- methano-4H-4-benzazonin-12-0l, M.P. 195-197 C.

EXAMPLE X To a stirring suspension of 3.48 grams (0.0918 mole) lithium aluminum hydride in 300 cc. dry tetrahydrofuran, a 9.8 gram (0.0306 mole) sample of 1,2,3,5,6,7-hexahydro 12 hydroxyimino-4-phenethyl-2,6-methano-4H-4- benzazonine dissolved in 100 cc. tetrahydrofuran is added. The reaction mixture is refluxed 6 /2 hours and then stirred at room temperature for 16 /2 hours. Cautiously cc. of water and 3 cc. of 25 percent sodium hydroxide are added and the resulting mixture after addition of ether is stirred at room temperature for one hour. The reaction mixture is filtered to give the filtrate which is evaporated to an oil. The oil is dissolved in ether, dried with magnesium sulfate and evaporated. The oily amine obtained is dissolved in ether and treated with 5 grams (0.0384 mole) of propionic anhydride. The reaction mixture is warmed on a steam bath for A2 hour, cooled and filtered. The precipitate is recrystallized from aqueous ethanol. The product obtained is 1,2,3,5,6,7-hexahydro-12- propionamido 4 phenethyl 2,6 methano 4H 4- benzazonine, M.P. 150151 C.

EXAMPLE XI To 1.43 grams (0.206 mole) of freshly cut lithium wire in 10 cc. ether, 16.2 grams (0.103 mole) of bromobenzene in 25 cc. ether is added at a rate so as to control refluxing. Upon complete addition the suspension is allowed to stir at room temperature one hour and then the mixture is treated with 50cc. benzene. The ether in the reaction mixture is removed by distillation. To the resulting reaction mixture, 10 grams (0.0344 mole) of 1,2,3,5,6,7 hexahydro 4-benzyl-2,6-methano-4H-4- benzazonin-lZ-one in 20 cc. benzene is added and allowed to reflux 1% hours and then allowed to stand at room temperature for 18 hours. After the large unused pieces of lithium are removed and destroyed, the reaction is treated with a saturated ammonium chloride solution. Chloroform is added and the resulting mixture is stirred at room temperature for /2 hour. The layers are separated and the aqueous layer is extracted several times with chloroform. The organic layer is combined with the chloroform extracts, dried with magnesium sulfate and evaporated to an oil which crystallizes upon cooling. The solid is recrystallized from methylcyclohexane. The product obtained is 4 benzyl 1,2,3,5,6,7-hexahydro-12-phenyl-2,6 methano-4H-4-benzazonin-12-01, M.P. 150-151 C.

EXAMPLE XII A 10 gram (0.0271 mole) sample of 4-benzyl-l,2,3,5, 6,7-hexahydro-12-phenyl-2, 6-methano-4H-4 benzazonin- 12-ol in 200 cc. glacial acetic acid containing 6 drops perchloric acid is hydrogenated at room temperature using 0.5 gram of 10 percent palladium-on-carbon as the catalyst. The catalyst is removed by filtration and the resulting filtrate is cautiously evaporated under reduced pressure to an oil. The oil is treated with ice and sodium bicarbonate giving a solid which is dissolved in chloroform. The chloroform solution is dried with magnesium sulfate and evaporated to an amorphous solid. The solid is recrystallized from anhydrous ethanol. The product is 1,2,3,5,6,7-hexahydro-12-phenyl-2,6-methano- 4H-4-benzazonin-l2-ol, M.P. 227-228 C.

EXAMPLE XIII Using the procedure of Example XII and substituting 4 benzyl 1,2,3,5,6,7 hexahydro 2,6 methano 4H 4 benzazonin 12 one for 4 benzyl 1,2,3,5,6,7- hexahydro 12 phenyl 2,6 methano 4H 4- benzazonin-lZ-ol, the product obtained is 1,2,3,5,6,7- hexahydro-2,6-methano-4H-4-benzazonin-12-01.

6 EXAMPLE XIV A 2 gram (0.00655 mole) sample of 1,2,3,5,6,7-hexahydro- 4 phenethyl 2,6 methano 4H 4 benzazonin-12-one in 75 cc. glacial acetic acid is hydrogenated at room temperature using 0.17 gram of platinum oxide as the catalyst. After removal of the catalyst by filtration, the resulting solution is evaporated under reduced pressure to an oil. The oil is dissolved in water and the aqueous solution is made definitely basic with 25 percent sodium hydroxide, giving an oily suspension. The suspension is extracted with ether and the ethereal extract is dried with magnesium sulfate and evaporated to an oil. The oil is dissolved in ether and treated with ethereal hydrogen chloride. On recrystallization from anhydrous ethanol-ether the product is 1,2,3,5,6,7- hexahydro 4 phenethyl 2,6 methano 4H 4 benzazonin-12-ol hydrochloride /s mole water), M.P. 186.5- 188.5 C.

I claim:

1. A member selected from the group consisting of compounds having the following structural formulae:

where in R is a member selected from the group consisting of hydroxyl and loweralkylcarbonylamido, R is phenyl when R is hydroxyl and R is hydrogen when R is loweralkylcarbonylamido; R and R taken together is a member selected from the group consisting of 0x0 and oximino; R is a member selected from the group consisting of benzyl and ,B-phenethyl; and

O=( N-Ra wherein R is a member selected from the group consisting of benzyl and ,B-phenethyl; and R and R are members individually selected from the group consisting of loweralkyloxycarbonyl; and the nontoxic acid addition salts thereof.

2. 1,2,3,5,6,7 Hexahydro 12 propionamido 4- phenethyl-2, 6-methano-4H-4-benzazonine.

3. 1,2,3,5,6,7 Hexahydro 12 phenyl 2,6 methano-4H-4-benzazonin-12-01.

4. Dimethyl 4 benzyl 1,2,3,5,6,7 hexahydro 12- oxo-2,6-methano-4H-4-beuzazonine-2,-6-dicarboxylate.

5. Dimethyl 1,2,3,5,6,7 hexahydro 12 oxo 4- phenethyl 2,6 methano 4H 4 benzazonine 2,6- dicarboxylate hydrochloride.

6. 4 benzyl 1,2,3,5,6,7 hexahydro 2,6 methano- 4H-4-benzazonin-12-one.

7. 4 phenethyl 1,2,3,5,6,7 hexahydro 2,6 methano-4H-4-benzazonin-12-one.

8. 1,2,3,5,6,7 hexahydro 12 hydroxyimino 4- phenethyl-Z,6-methano-4H-4-benzaz0nine.

9. 4 benzyl 1,2,3,5,6,7 hexahydro 12 phenyl- 2,6-methano-4H-4-benzazonin-12-01.

and

No references cited HENRY R. JILES, Primary Examiner G. T. TODD, Assistant Examiner US. Cl. X.R. 

